Global profiling reveals common and distinct N6-methyladenosine (m6A) regulation of innate immune responses during bacterial and viral infections.

N-methyladenosine (mA) is a dynamic post-transcriptional RNA modification influencing all aspects of mRNA biology. While mA modifications during numerous viral infections have been described, the role of mA in innate immune response remains unclear. Here, we examined cellular mA epitranscriptomes during infections of Pseudomonas aeruginosa and herpes simplex virus type 1 (HSV-1), and lipopolysaccharide (LPS) stimulation to identify mA-regulated innate immune response genes. We showed that a significant portion of cellular genes including many innate immune response genes underwent mA modifications in 5'UTR and 3'UTR. We identified common and distinct mA-modified genes under different stimulating conditions. Significantly, the expression of a subset of innate immune response genes was positively correlated with mA level. Importantly, we identified genes that had significant enrichments of mA peaks during P. aeruginosa infection following knockdown of mA "eraser" ALKBH5, confirming the regulation of these genes by mA and ALKBH5. Among them, we confirmed the association of mA modification with gene expression in immune response genes TNFAIP3, IFIT1, IFIT2 and IFIH1. Taken together, our results revealed the vital role of mA in regulating innate immunity against bacterial and viral infections. These works also provided rich resources for the scientific community.